Drug-Induced and Toxic Disorders in Neuro-Ophthalmology

Chapter 17 Drug-Induced and Toxic Disorders in Neuro-Ophthalmology

E. Zrenner and W. Hart

Signal processing in the retinal photoreceptors, as well as in the cells and synapses of the afferent visual pathways, is controlled by a group of neurotransmitters, proteins, enzymes, and their metabolites that arise in complex cascades of chemical reactions to produce all the necessary functions of normal visual perception. Neurotropic drugs, toxins and some foods can interfere with these processes and their underlying structural components, thereby disturbing visual perception. In addition, there are non-neural metabolic processes that are needed to maintain the integrity of the visual system. For example, pigment epithelial cells, glial cells, and vascular components of the afferent visual pathway are all susceptible to the effects of drugs, toxins, and some foods. This mechanism is often responsible for subjective alterations in visual perception that are either expressed symptomatically by the patient or detected by specific visual function tests. Since a very large number of substances can specifically damage vision, we can discuss only the general principles of the diagnosis and management of toxic visual disorders. For individual cases of known or suspected toxic damage to vision, standard sources of reference should be consulted (see “Further Reading” at the end of the chapter). This chapter describes the cell-specific disturbances of visual function, providing a rational basis for understanding toxic visual disorders, and outlines the typical symptoms of drug side effects that affect vision. This is meant to give the clinician a rational basis for diagnostic testing in cases of suspected toxic damage to the visual system.

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Cell-Specific Alterations Photoreceptors of Visual Function Numerous substances can alter the phototransduction pro- Retinal Pigment Epithelium cess by affecting individual steps of its enzymatically driven cascade. Common agents include the cardiac glycosides The retinal pigment epithelium (RPE) has four principal and chloramphenicol. The following are a few examples. functions: (1) phagocytosis, (2) vitamin A transport and storage, (3) control of retinal potassium content, and (4) Inhibitors of Phosphodiesterase protection from the effects of phototoxicity. So, RPE func- Sildenafil (Viagra) acts as an inhibitor of phosphodiester- tion can be damaged by inhibitors of phagocytosis, by drug ase (PDE) and can influence phototransduction when used dependent changes in cellular metabolism, by vitamin A at higher therapeutic doses. The effect is transient and deficiency or excess, and by substances that bind to mela- quickly reversible. Other drugs with similar effects on PDE nin. include theophylline and related agents used in the man- The melanin granules of the RPE bind tightly to certain agement of cardiopulmonary diseases. substances, such as phenothiazines, glycosides, and anti- Pearl malarial drugs such as chloroquine phosphate. This group • also includes primaquine, pyrimethamine (Daraprim) and Potential visual effects of PDE inhibitors include daz- hydroxychloroquine (Plaquenil). Chloroquine phosphate zling photophobia, a blue discoloration of contrasting binds strongly to the RPE with a half-life of 5 years, 80 times borders, dyschromatopsia (loss of hue discrimination), more strongly than it binds to the liver. This drug is not and phosphenes. used for malarial prophylaxis alone, but it also plays an important role in the treatment of rheumatoid diseases (up The differing spectral absorption properties of the retinal to 4 mg/kg, or for hydroxychloroquine 6 mg/kg of body cones (short, long, and intermediate wavelength light sen- weight per day). At these maximal rates, a critical cumula- sitivity) are the basis for a variety of color vision distur- tive dose may be reached within 6 months. bances: erythropsia, chloropsia, and tritanopsia. Signs of chloroquine phosphate retinopathy (typically following a cumulative dose of 100 to 300 g) are: ! Note ■ A relative paracentral scotoma, usually an annular peri- Chromatic sensations (Chromatopsia) and changes in foveal ring-shaped depression color perception are among the earliest signs of drug- ■ Loss of blue/yellow color discrimination induced visual disorders. ■ RPE depigmentation in a target pattern matching the ring-shaped visual field depression (most easily seen Calcium Antagonists and Cardiac Glycosides during fluorescein angiography as window defects) Calcium channel blockers and cardiac glycosides can affect ■ Reduced electrooculography (EOG) potentials control of intracellular calcium content, changing the light ■ Reduced b-wave amplitudes and prolonged latencies of adaptation properties of retinal photoreceptors. The chang- ERG responses (limited to relatively advanced cases) es, however, are transient and reversible, and (in contradis- ■ Depigmentation of the RPE in a ring-shaped pattern tinction to chloroquine) these drugs affect function in a surrounding the fovea relatively benign manner. Occasionally they produce symp- ■ A bull’s eye or target-shaped maculopathy becomes vis- toms of phosphenes, but in most cases, patients are unaware ible without special testing, but only in the later stages of the changes in their color vision. Detection of these hue of irreversible visual loss discrimination deficits requires specific visual function tests of color perception, such as the desaturated Farn- Particularly susceptible are those patients with low body sworth D-15 (relatively cheap, quick, and easy), the Farn- weight and/or poor renal function. Care should be taken to sworth-Munsell 100 hue, or the Nagel anomaloscope (rela- avoid overdosing. tively expensive, slow, and difficult). A number of testing Chemotherapeutic agents that disrupt protein metabo- devices are available that are intended to reduce the time lism have an effect similar to the retinal toxicity of the needed to evaluate hue discrimination, but there has been antimalarial drugs. These include vincristine, vinblastine, only limited study of their clinical effectiveness. alkylating agents, and some neurotoxic antibiotics, such as streptomycin and its associated derivatives.

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Phenothiazine mates that have been given toxic doses of lead have shown Phenothiazine and related drugs have been widely adopted significant morphological changes in rod photoreceptors in the clinical management of the various psychoses. This and their afferent retinal pathways. group includes chlorpromazine, trifluoperazine (Stelazine), and promethazine. These drugs, when used chronically and in therapeutic doses, cause night blindness and retinal Retinal Ganglion Cells pigment dispersion, a consequence of damage to rod outer segments. Retinal ganglion cells serve a diversity of neural tasks: the parvocellular system of cone dominated (and small) ganglion cells mediates the perception of color and the higher Bipolar Cells, Horizontal Cells, and Amacrine Cells levels of spatial acuity, while the magnocellular ganglion cells respond to changes in visual stimuli involving image The outer and inner layers of the retina have numerous motion and contrast. Drugs that affect glial cell function, neurotransmitters and modulating substances (e.g., gam- e.g., ethambutol, can lead to a variety of changes in the ma-aminobutyric acid [GABA], glycine, acetylcholine, parvo- and magnocellular systems. dopamine, serotonin, substance P, vasoactive intestinal Pearl peptide [VIP], somatostatin, nitric oxide [NO], and angio- • tensin-converting enzyme [ACE]). Altering the metabo- Ganglion cell damage by ethambutol/myambutol leads lism, release, or uptake of these substances can affect visual to: function. The following section discusses several common ■ Acquired dyschromatopsias (best found with the examples. desaturated Farnsworth D-15 test), which are an early symptom Alteration of GABA Metabolism ■ Changes in color matching by anomaloscopic mea- by Antiseizure Medications sures (not ordinarily available in most clinical set- Some drugs used in the treatment of epilepsy can alter the tings) metabolism of GABA, leading to disturbances of visual ■ Loss of contrast perception function. These drugs, includingcarbamazepine (Tegretol), ■ Visual field loss (constriction and/or central and phenytoin (Dilantin), and vigabatrin (Sabril), are known to cecocentral scotomas) disturb color vision, as measured by hue discrimination ■ Loss of acuity tests like the Farnsworth D-15. Vigabatrin can produce irreversible, concentric, peripheral visual field loss. Drugs Several months after cessation of ethambutol use, normal that alter GABA metabolism are also likely at fault for visual function often returns if optic atrophy has not al- changes in contrast perception by influencing the function ready developed. Other agents that can lead to ganglion cell of retinal horizontal cells. Chronic use of such agents can disease include chloramphenicol, methanol, quinine, thal- also lead to irreversible loss of these visual functions. It is lium, and ergotamine derivatives. advisable that patients on high doses or long-term use of these drugs be seen regularly for ophthalmic visual testing. Retinal Glial Cells Alteration of Dopamine Metabolism by Drugs and Heavy Metals The retina has several types of glial cells:Müller cells, oligo- Many drugs that are known to affect the metabolism of dendrocytes, and astrocytes. Müller cells are important for dopamine can produce changes in retinal function. Anti glutamate metabolism (in the uptake of the transmitter re- psychotic drugs, such as phenothiazine, haloperidol, and leased by photoreceptors), as well as for the storage of cal- dopamine D2 antagonists are known to produce changes in cium ions. Damage to glial cells, e.g., by the ammonia tox- retinal function. Similarly, heavy metal intoxication, by icity of the alcohol syndrome (caused by severe hepatic lead for instance, hinders the activity of dopamine synthe- damage), produces marked changes in the electroretino- sis. Since dopamine is of central importance in the function gram (ERG). This arises as the result of damage to Müller of rod-specific amacrine cells (A II amacrine cells) heavy cells, since the b-wave of the ERG is strongly determined by metal poisoning results in changes to rod dominated neural the function of the retina’s Müller cells. A common symp- signaling in the retina, as reflected in the detectable altera- tom of altered color perception in this setting is an acquired tions to scotopic ERG potentials or in contrast sensitivity. tritanopia: loss of discrimination between hues that differ Histologic preparations of the retinas of nonhuman pri- in their blue/yellow content.

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Optic Nerve endocrinologic or toxicologic disorders. It is particularly important to discover any history of prior disease. If he- Varieties of drugs have specific effects on the function of patic or renal function are known to have been compro- axonal transport. Lead poisoning, for example, leads quick- mised, it is possible that some drugs will not have been ly to the appearance of disc edema, concentric loss of visual metabolized or completely excreted, leading to toxic blood field, and a loss of blue perception. In higher doses,etham - levels. In such cases, a parallel evaluation by the patient’s butol produces a toxic demyelination of ganglion cell axons, primary care physician or internist is important. Following leading to a loss of optic nerve function, as detected by a gastric resection or bypass procedures, the risk of a vita- loss of amplitude in visually evoked potentials, the devel- min-deficiency syndrome increases, and may be the cause opment of central and cecocentral scotomas, and acquired of a metabolic optic atrophy, e.g., by chronic vitamin B12 dyschromatopsias. Similarly, damage to optic nerve func- deficiency. tion is produced by the toxic effects of isoniazid (INH), Determining the duration of prior periods of illness streptomycin, and chloramphenicol. will help to rule out chronic overdosing of medications as a mechanism for visual loss. It is important to determine the doses and durations of use for particular medications, Central Nervous System including antitubercular agents, such as ethambutol, and antimigrainous agents, such as the ergot alkaloids, which As has been outlined for retinal disorders, toxic and phar- often produce disturbances of red/green hue discrimina- macologic disturbances of visual function can also crop up tion. Chronic use of antimalarials in the treatment of rheu- in the central nervous system. In addition to neurotropic matologic diseases can result in damage to retinal mecha- effects, many drugs can cause elevations in intracranial nisms for blue/yellow hue discrimination. A history of drug pressure, resulting in papilledema, such as following the use should include specific questions about the taking of administration of ergotamine (see below). analgesics, antibiotics, neuroleptics, cardiac glycosides, an- tiarrhythmics and antihypertensives, as well as sleeping medications (■ Table 17.1). Acquired color vision distur- From Signs and Symptoms to Diagnosis bances associated with these drugs are summarized in ■ Table 17.3. General Medical History • Pearl A detailed medical history is critically important for cases Tobacco use of only 30 g weekly can produce a form of in which toxic or pharmacologic effects on vision are sus- cyanide intoxication, especially when hepatic detoxifi- pected. Malabsorption syndromes, accompanied by chang- cation of trace cyanide is weakened by chronic liver es in color perception, can be early indications of meta- disease (alcoholism and heavy tobacco use are familiar bolic diseases and lead to further investigation of possible companions).

Table 17.1. Presentation, etiologic considerations, and diagnostic strategies to use when drugs, alcohol, occupational, and/or recrea- tional exposures are a suspected source of toxic damage to vision

Presentation Etiologic considerations Diagnostic strategies Medications: Phagocytosis inhibitors, transmitter Analgesics, antibiotics, psychotropic drugs, metabolism, faulty phototransduction, cardiovascular drugs, sleeping agents disturbance of pupillary function

Tobacco/alcohol Optic neuropathy, cyanide poisoning B12 blood levels, B12 absorption, (trace) Schilling test Occupational exposure Heavy metals, solvents, chemicals Intoxication, retinal edema, inhibition Toxicologic tests, bone marrow smears in workplace, excessive light exposure of mitochondrial oxidase enzymes, (especially when lead poisoning disturbances of accommodation is suspected), fluorescein angiography Pastime activities Exposure to solvents in poorly ventilated Intoxication rooms, gardening (pesticides)

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Vitamin B12 deficiency, as in megaloblastic anemia, can disorders, while a history of stable deficits in vision is more lead quickly to a metabolic optic neuropathy. Careful static consistent with a heredofamilial disorder. Retinal degen- perimetry of the central visual field is particularly helpful erations most often have a gradually increasing course of at uncovering the characteristic shape, size, and location of visual loss; toxic disorders present as bilaterally symmetric scotomas that are sharply defined, often lancet-shaped and diseases; and nontoxic, acquired diseases (vascular, inflam- deep, extending linearly from the nasal border of the phys- matory, or neoplastic) are more often asymmetric. Loss iologic blind spot to the point of fixation (see Chap. 4). Of- of vision with clear refractive media in company with an ten the risk of toxic disease is discovered when taking a acquired dyschromatopsia suggests a toxic disorder. history of occupational exposures. Chronic exposure to heavy metals like lead and silver that are common in metal ! Note working industries or in commercial printing plants, can Other symptoms frequently associated with toxic am- lead to a toxic optic neuropathy that becomes apparent, aurosis include paresthesias, headache, vertigo and loss sometimes years after leaving the trade. Skeletal accumula- of hearing. tion of lead can sometimes be found through careful radio- logic study. Blood levels of lead that are often only margin- ally elevated can cause an optic neuropathy following years Important Details of chronic exposure. Inhalation of solvent vapors like ben- of the Ophthalmic Examination zene or methyl alcohol can lead to occupationally acquired dyschromatopsias. Another occupational hazard to be con- When neuro-ophthalmic problems are recognized or sus- sidered is that of retinal phototoxicity, as for operators of pected, the basic ophthalmic examination should give as instruments with very powerful light sources (e.g., labora- much weight to evaluating eye movements, pupillary func- tory engineering instruments, lasers, or photo projectors). tion, and accommodation, as it usually does to deposits on lens, iris, and corneal surfaces. Ophthalmoscopy may find the toxic effects of drugs (e.g., narcotics containing me- Some Peculiarities of the Ophthalmic History thoxyflurane ormethadone) that are metabolized into oxa- lates, resulting in deposits with an albipunctate appearance, Additional consideration should be given to some specifi- often described as a talc“ retinopathy.” Macular edema and cally ophthalmic problems, as outlined in ■ Table 17.2. As- toxic optic neuropathies with associated optic disc pallor sessment of the duration and course of illness can help to can be produced by some medications, such as during the differentiate between congenital and acquired forms of course of therapy with antibiotics like chloramphenicol, visual loss. Acute processes are more likely to be acquired and tetracycline.

Table 17.2. Typical ophthalmic presentation in cases of intoxication or drug side effects, etiologic considerations, and diagnostic strategies

Ophthalmic presentation Etiologic considerations Diagnostic considerations and strategies

Duration/course Acute: more likely acquired Chronic and stable: more likely heredofamilial Tobacco/alcohol abuse Occupational intoxication less likely Strict symmetry Intoxication more likely Hemeralopia with clear ocular media Intoxication or heredofamilial retinopathy Electrophysiology and/or dark adaptometry Nyctalopia Tapetoretinal degenerations Electrophysiology or intoxication possible and/or dark adaptometry Dyschromatopsias Vascular, toxic, demyelinating, and compressive Internal medical optic neuropathies, and/or retinopathies and/or neurological consultation

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• Pearl no blue cones in the fovea, and their density is greatest at Optic disc edema and elevated intracranial pressure are about 2.5° of retinal eccentricity. Toxic retinopathy com- known to be produced in some patients by the systemic monly presents as a loss of perifoveal visual field (ring- administration of corticosteroids, nalidixic acid, tetra- shaped scotoma), which in turn produces greater impair- cycline, and toxic doses of vitamin A. Exposure to hexa- ment of blue/yellow than of red/green hue discrimination. chlorophene, dinitrobenzene, dinitrochlorobenzene, A drug that commonly causes this pattern of damage is disulfiram, INH, thallium, and vincristine can cause a chloroquine. The patient will notice problems with reading combined optic neuropathy and peripheral neuropathy. that are far greater than one would expect, based on their retained foveal function and good Snellen acuity. The paracentral loss of vision disrupts the fluency of reading, since Clinical Workup of Suspected Toxic Disorders only letters and syllables can be seen, rather than whole words or phrases (see Chap. 24 for a more complete expla- The most important signs and symptoms that are likely to nation). Hue discrimination tests (such as the desaturated be present when dealing with a toxic disorder include loss Farnsworth D-15) will find a greater impairment of blue/ of Snellen acuity, color vision impairment, changes in the yellow discrimination with preservation of red/green dis- ERG/EOG/visually evoked potentials (VEP), visual field crimination. constriction (organic, not functional), photophobia, and Drugs like ethambutol, however, damage the pathways poor dark adaptation. fed by foveal cones, resulting in an early loss of Snellen acuity and relative or absolute central scotomas. Since the fo- Loss of Acuity and Central Scotoma veal cone matrix of red- and green-sensitive cones is devoid There are a number of substances that preferentially dam- of blue cones, damage to the fovea or its afferent projections age the papillomacular bundle and its retrobulbar axons, (with at least some preservation of the extrafoveal portions causing central scotomas and loss of Snellen acuity. of the central visual field) results in a dyschromatopsia marked by loss of red/green hue discrimination and with Pearl • relative preservation of blue/yellow hue discrimination. The most important of these include barbiturates, ben- Again, the Farnsworth D-15 test is not prohibitively time- zene, lead, tobacco-alcohol syndrome, ethambutol, and consuming, and it will detect a preferential loss of red/green methanol. hue discrimination. These patterns of changes in color vision are characteristic of the early stages of retinal or neural Loss of Peripheral Visual Field toxicity, at a time when their detection is most valuable. Agents that typically damage the peripheral visual field, Progression of the damage, causing a scotoma that erases without necessarily affecting acuity, include lead nalidixic the central 5 to 10° of visual field, results in an anarchic loss acid, phenothiazine, vigabatrin, chloramphenicol, nitrofu- of color perception with no useful hue discrimination at all. rantoin, quinine, and the salicylates. Ring and arcuate sco- Typically, if acuity has already been reduced to 20/200 or tomas are typically associated with chloroquine, INH, and worse, hue discrimination tests will be of no value. Thus, streptomycin. color vision testing of this sort is best for evaluating patients in the early stages of their diseases, but may become useless Change in Color Vision as the visual damage progresses. The use of color vision test- An acquired dyschromatopsia is frequently the presenting ing in congenital and acquired dyschromatopsias is dis- finding of toxic damage to the retina and/or optic nerve. cussed more completely in Chap. 6. The principal drugs and chemical agents associated with damage to color vision are summarized in ■ Table 17.3. Reduced Contrast Sensitivity The toxic dyschromatopsias are associated with damage to and/or Photophobia the function of the three types of cone photoreceptors Agents that depress neural function in a general way often (short-wavelength-sensitive blue cones, medium-wave- produce a loss of contrast sensitivity. When the effect is length-sensitive green cones, long-wavelength-sensitive most pronounced in the central visual field, patients will red cones) or to their downstream neurons. The toxic effect often complain of severephotophobia. This is due to loss of on color vision is determined in part by the variable densi- the cone-dominated portions of the visual field with pres- ties of cones, and by variable susceptibility of the down- ervation of the rod-dominant portions. In this case, suffer- stream ganglion cell axons to toxic damage. ers can see comfortably at low levels of illumination, but For example, blue cones have a particular spatial distri- they are effectively blinded at higher levels of brightness bution in the retina unlike any other cone system: There are (hemeralopia).

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Table 17.3. Common drug-induced disturbances of color vision. (Expanded from data reported by Pokorny et al. 1979)

Medication Type I Type II Type III Acquired protan Acquired deutan Acquired tritan red/green red/green blue/yellow dyschromatopsia dyschromatopsia dyschromatopsia

Antidiabetics (oral) + Antipyretics + Phenylbutazone + Nitrofurantoin and its derivatives + + Nalidixic acid – Phenothiazine +? + Quinoline and its derivatives + + + Quinine + + Sulfonamides + Tuberculostatics + Dihydrostreptomycin + Ethambutol + Isoniazid + PAS + Streptomycin + Arsenic + Chloramphenicol + Cyanide + Digitalis ++ + + Disulfiram + Ergotamine + Erythromycin + Ethanol + Indomethacin + Lead + MAO inhibitors + Indomethacin + Sildenafil + Thallium + Trimethadon + Vincristin +

PAS Para-aminosalicylic acid, MAO monoamine oxidase

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Abnormal ERG glaucoma in eyes with narrow chamber angles. Mydriasis Disturbances of the phototransduction processes and/or of can occur following the use of antiparkinsonian medica- the synaptic processing in the retinal neuronal network are tions, some antihistamines, tranquilizers, antipsychotic easily detectable by ERG testing. Changes in the ERG often and antidepressant medications, and miosis can be pro- allow a distinction between rod- and cone-dominated dam- duced by cholinesterase inhibitors (used in the manage- age caused by toxic exposures. Reduced amplitude and pro- ment of myasthenia), antihypertensive agents, and opium longed latency of ERG responses are typical signs of retinal derivatives. Presenting symptoms caused by changes in toxicity and can be used to evaluate known or suspected refraction and/or accommodation are known to occur in toxic damage. Agents that often affect the ERG include response to the use of a number of medications. Thus, the phosphodiesterase inhibitors like sildenafil, phenothiazine use of an anticholinergic or adrenergic agent can lead to a and some tricyclic agents (thioxanthene derivatives), halo- loss of dioptric power in the lens and a reduction in the peridol, diazepam, imipramine, trimethadione, and others. amplitude of accommodation in addition to producing a pupillary mydriasis. Parasympathomimetic and sympatho- Abnormal EOG lytic agents by contrast can lead to a spasm of accommoda- The EOG provides specific information about the function with increasing dioptric power of the lens and an tion of the pigment epithelium/photoreceptor complex, associated miosis. Systemically administered agents must and is especially useful for detecting pigment epithelium be given at unusually high doses to cause these problems in damage of the kind produced by the antimalarial drugs, most people, but some patients have a heightened suscep- such as chloroquine (Aralen) and hydroxychloroquine tibility by virtue of anatomically narrow anterior chamber (Plaquenil). angles, for instance.

Abnormal VEP • Pearl Toxins that damage the myelin sheaths of ganglion cell Acutely transient myopia without miosis or spasm axons (e.g., ethambutol, lead), especially those that have of accommodation can also occur in patients taking their greatest effect on the papillomacular bundle, produce salicylates, codeine, sulfonamides, tetracyclines, some changes in visually evoked cortical potentials. Looking for diuretics, carbonic anhydrase inhibitors, and some an- these changes with the VEP test is particularly valuable tipsychotic medications. when monitoring long-term use of drugs like ethambutol. Abnormal Lid and/or Eye Movements Abnormal Dark Adaptation Ptosis has been reported as a side effect after the use of bar- Drugs like vincristine or those of the phenothiazine group biturates and other hypnotic or sedative agents, such as commonly cause a depression of light sensitivity and a chloral hydrate, as well as by heavy metals, vinca alkaloids, change in the shape of the dark adaptation curve. These muscle relaxants, and sympatholytic and ganglionic block- agents cause damage to the pigment epithelium/photore- ing agents. ceptor complex, alter the kinetics of the rhodopsin cycle, Blepharospasm and involuntary blinking can be signs and change the synaptic behavior of horizontal cells, ag- of chronic poisoning by cholinesterase inhibitors, such as gravating the problems with dark adaptation. When such a the organophosphate insecticides like Malathion. A widen- drug side effect is suspected, a very careful drug history and ing of the palpebral fissures with upper lid retraction may ophthalmic examination should give a clue as to the agent, be a sign of drug-induced hypersympathotonia following the site, and the mechanism of toxic damage to vision. ingestion of amphetamines. Hypermetric saccades can be brought out by overdoses of monoamine oxidase (MAO) Abnormal Pupils inhibitors, while slowing of eye movements can be seen Directly acting adrenergic agents, such as adrenalin and following intravenous administration of central nervous phenylephrine, as well as indirect adrenergic agents, such system depressants like the benzodiazepines. as tyramine and cocaine, stimulate pupillary dilation, while Higher-order centers of eye movement control are af- cholinergic agents, such as pilocarpine and physostigmine, fected by a very large number of drugs, but most common- stimulate pupillary constriction. ly by sedatives and anticonvulsants. Even relatively low Anticholinergic agents block neural transmission at doses of these agents can cause substantial changes in eye parasympathetic terminals, leading to pupillary dilation. movements, especially when the affected patient is already This group includes a number of antispasmodic agents ill. Careful history taking of drug use and access to appro- used to reduce gastrointestinal motility, as well as the bel- priate reference materials are sometimes necessary for cor- ladonna alkaloids, that pose a threat of acute angle closure rect diagnosis of an iatrogenic problem.

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Conclusion to build a circumstantial case. Occasionally, contact with a poison emergency call line (■ Table 17.5) or with a manu- Binocular visual disturbances of uncertain origin (■ Ta- facturer of the suspected agent can be helpful. For suspect- ble 17.4) can have many different causes, including the un- ed occupational exposures, contact with an industrial insti- intentional side effects of medications and/or exposure to tute of labor medicine can often uncover previously unrec- environmental toxins. The retina and afferent visual path- ognized risks to health. When the suspicion of toxic expo- ways, by virtue of their many neuronal functions, often act sure is persuasively strong, reports should be filed with the as an early warning system of threatening exposures to tox- appropriate state and local governmental agencies. Most ins. The ophthalmologist has available a large number of important for the managing ophthalmologist is to at least instruments for the detection of these signs. Nevertheless, consider the possibility that there is a toxic cause of the in specific instances of suspicion, a direct causation can be visual problem, and to initiate the use of appropriate tests difficult to prove, requiring a detailed assembly of findings to better clarify the cause.

Table 17.4. Binocular visual disturbances of uncertain cause

Historical features to explore Are objective signs found?

Drugs: Frequent signs include: l Which? Dose? How Long? l Loss of visual acuity? l Change in color appearances? Toxic exposures: l Visual field defects? l Occupational? Ingested? l Poor dark adaptation? l Known diseases that affect absorption l Is the ERG, EOG, or VEP altered? or metabolism of toxins? l Unusual diet?

Are there characteristic ophthalmic symptoms? Additional clues to examine: l Photophobia? l Change in pupillary function? l Altered color perception? l Loss of accommodation? l Visual field loss? l Motility disturbance? l Blurred vision?

Are there characteristic neurologic symptoms? Classify by known associations: l Paresthesias? l Consult toxicologic reference texts (Grant and Schumann 1993). l Syncope? l Call your local poison control center (use the following URL l Headache? to find the nearest help: http://www.aapcc.org/findyour.htm). l Hearing loss? l Call the manufacturer of the suspected substance, if known.

For occupational exposures: l Consult with occupational physician. l File reports with local departments of health.

ERG electroretinogram, EOG electrooculogram, VEP visually evoked potential

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Table 17.5. Poison control centers

Given the numerous possibilities for agents in any case of intoxication, it is important to consult, in addition to the standard reference texts like W. Morton Grant’s Toxi cology of the Eye (W.M. Grant and J.S. Schuhman, Charles C Thomas Pub., Ltd., 4th edition, August 1993), databases of both ophthalmic and systemic drug- and toxin-induced disorders. The following internet resources can be of help:

l http://www.cdc.gov/niosh/homepage.html is a very good source of information about toxins as occupational hazards. The site is maintained by the National Institute for Occupational Safety and Health (NIOSH) and is a part of the Centers for Disease Control and Prevention (CDC)

l http://www.eyedrugregistry.com is the Web address of the National Registry for Drug-Induced Ocular Side Effects: National Registry of Drug-Induced Ocular Side Effects 3375 SW Terwilliger Blvd. Portland, OR 97239-4197, USA l http://www.nei.nih.gov/ The National Eye Institute provides convenient and useful links to multiple sources of information about toxicology, as it relates to vision. l http://toxnet.nlm.nih.gov/ is a good starting point when searching for known toxins, this site links to a wide range of databases for toxicology, hazardous chemicals, and related subjects. The various databases can be searched in unison, providing a convenient and comprehensive source of information. l http://www.druginfozone.org/ – In the UK this web site [as described by M. Wake and L. Lisgarten at http://pfonline.com/students/tp2001/internet/html] is run by the London and South Eastern Drug Information Service. It provides up-to-date news, current awareness bulletins, and monthly updates on the latest published material for 44 major drug topics such as drug interactions, pain, and poisoning. The material for these topics is taken from the Pharm-line database, which indexes English language pharmaceutical and medical journals. It has a very good links page.